Derivatives of glycinergic r(+)-2-amino-3-hydroxypropanoic acid

ABSTRACT

The use of R(+)-2-amino-3-hydroxypropanoic acid derivatives, nitrogen substituted by a (C 1 -C 6 )alkyl, (C 3 -C 6 )alkenyl, 3-oxo(C 5 -C 6 )alkyl, 3-oxo(C 4 -C 6 )alken-2-yl, phenyl(C 1 -C 6 )alkyl, phenyl(C 2 -C 6 )alkenyl, gem-diphenyl(C 1 -C 6 )alkyl, gem-diphenyl(C 2 -C 6 )alkenyl, (C 1 -C 6 )alcanoyl, optionally N-substituted alanyl, optionally N,N′-disubstituted lysinoyl, phenyl(C 1 -C 6 )alkylydene or gem-diphenyl(C 1 -C 6 )alkylidene group, and of the pharmaceutically acceptable salts thereof, for preparation of medicaments intended for the treatment of CNS diseases due to reduced glycinergic transmission, particularly for the treatment of autism, schizophrenia and Alzheimer&#39;s disease, is described.

OBJECT OF THE INVENTION

The present invention concerns the use ofR(+)-2-amino-3-hydroxypropanoic acid derivatives for preparingmedicaments for the treatment of Central Nervous System (CNS) diseasesdue to reduced glycinergic transmission, pharmaceutical compositionscomprising new R(+)-2-amino-3-hydroxypropanoic acid derivatives asactive principles, as well as new R(+)-2-amino-3-hydroxypropanoic acidderivative compounds.

BACKGROUND OF THE INVENTION

Following the discovery of the glycine binding site coupled to the NMDAreceptor at the level of CNS, it has been suggested that a deficiency inglycinergic and/or glutaminergic transmission at the level of the NMDAreceptor is one of the causes of diseases that involve cognitive andmemory disorders such as autism, children learning disorders,schizophrenia and Alzheimer's disease.

Substances which are capable of enhancing glycinergic transmission arethus able of improving the cognitive disorders and mnestic disordersaccompanying these diseases.

PRIOR ART

It is known that glycine is one of the most powerful agonists of theNMDA glycine site receptor and that other D-aminoacids, includingD-serine, are very good agonists, but with a weaker affinity than thatof glycine. An abstract journal on the subject was published in CNS DrugReviews, 1995, 1(2), 227-260.

It is also known that the negative and cognitive symptoms ofschizophrenia can be treated with glycine or with its precursors or evenwith glycine reuptake antagonists. In particular, documents U.S. Pat.No. 5,837,730 and U.S. Pat. No. 5,854,286 teach that very high oraldoses (>30 g/day) of glycine or of compounds inducing elevations in CNSglycine level by serving as glycine precursors or which would substitutefor glycine at the glycine site of the NMDA complex, lead to animprovement in the negative symptoms in schizophrenic patients. Amongthese compounds, the documents mention glycinamide, threonine andD-serine.

U.S. Pat. No. 6,228,875 shows that neuropsychiatric diseasescharacterized by a deficiency in neurotransmission by NMDA receptor canbe alleviated by means of a composition acting as an agonist of theglycine site on NMDA receptor. Among these agonists, said documentnotably mentions D-serine, D-serine esters, alkylated D-serine orD-serine precursors. The same document describes a double-blind clinicaltrial in which D-serine, administrated at a dose of 2 g/day, iseffective in the treatment of schizophrenia, even in patients havinglittle response to conventional antipsychotic drug treatment. Theresults of the study described in this document lead to the conclusionthat D-serine, which despite having a lower affinity than glycine isclinically active in a dose 15 times weaker than that expected forglycine, is undoubtedly not just a mere glycine substitute.

SUMMARY OF THE INVENTION

Now it has been discovered that D-serine derivatives, namelyR(+)-2-amino-3-hydroxypropanoic acid derivatives, evaluated inpredictive tests for an improvement in the activity of glycinergictransmission, have proven to be superior to D-serine.

More particularly, it has been found thatR(+)-2-amino-3-hydroxypropanoic acid, substituted on nitrogen with a(C₃-C₆)alkenyl, 3-oxo(C₅-C₆)alkyl, 3-oxo(C₄-C₆)alken-2-yl,phenyl(C₁-C₆)alkyl, phenyl(C₂-C₆)alkenyl, gem-diphenyl(C₁-C₆)alkyl,gem-diphenyl(C₂-C₆)alkenyl, (C₁-C₆)alcanoyl, optionally N-substituted2-aminopropionyl, optionally N,N′-disubstituted 2,6-diamino-n-hexanoyl,phenyl(C₁-C₆)alkylidene or gem-diphenyl(C₁-C₆)alkylidene group,notwithstanding its lower content in D-serine, is able to improve theglycinergic transmission in patients suffering from CNS diseases due toreduced glycinergic transmission, particularly patients suffering fromautism, schizophrenia or Alzheimer's disease, in much weaker doses thanthose used for glycine and at the most as high as those used forD-serine.

It has also been found that, among said R(+)-2-amino-3-hydroxypropanoicacid derivatives, optionally esterified R(+)-2-amino-3-hydroxypropanoicacid, N-substituted by an alkyl group having at least one optionallysubstituted phenyl radical, has a higher in vivo activity than that ofD-serine and of its alkylated derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Thus, according to one of its aspect, the present invention concerns theuse of a R(+)-2-amino-3-hydroxypropanoic acid derivative of formula I

wherein Ra is a hydrogen, Ra′ is a hydrogen, a straight or branchedchain (C₃-C₆)alkenyl, 3-oxo(C₄-C₆)alkyl or 3-oxo(C₄-C₆)alken-2-yl group,a phenyl(C₁-C₆)alkyl, phenyl(C₂-C₆)alkenyl, (C₂-C₆)alcanoyl,gem-diphenyl(C₁-C₆)alkyl, gem-diphenyl(C₂-C₆)alkenyl, (C₃-C₆)alkenoyl,R(+)-2-aminopropionyl, S(−)-2-aminopropionyl,N-(C₂-C₆)alcanoyl-R(+)-2-aminopropionyl,N-(C₂-C₆)alcanoyl-S(−)-2-aminopropionyl,N-benzyloxycarbonyl-R(+)-2-aminopropionyl,N-benzyloxycarbonyl-S(−)-2-aminopropionyl, R(+)-2,6-diamino-n-hexanoyl,S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-(C₂-C₆)alcanoyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-(C₂-C₆)alcanoyl-S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-S(−)-2,6-diamino-n-hexanoyl group; or Ra andRa′ are together a phenyl(C₁-C₆)alkylidene orgem-diphenyl(C₁-C₆)alkylidene group; Ra″ is a hydrogen, a straight orbranched chain (C₁-C₆)alkyl or a (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,phenyl(C₁-C₂)alkyl, phenacetyl or phenyl group, the phenyl group orgroups present in the Ra, Ra′ and Ra″ substituents being non-substitutedor substituted by a halogen atom or by an hydroxy, (C₁-C₃)alkoxy, cyano,nitro or acetyl group, with the proviso that, when Ra and Ra′ are bothH, then Ra″ is other than hydrogen, methyl or ethyl; or of apharmaceutically acceptable salt thereof, for the preparation ofmedicaments for the treatment of cognitive disorders or mnesticdisorders which accompany CNS diseases due to a reduced glycinergictransmission, particularly for the treatment of autism, schizophreniaand Alzheimer's disease.

Among the compounds of formula I wherein Ra′ is agem-diphenyl(C₁-C₆)alkyl group, those in which Ra′ is aω-diphenyl(C₂-C₆)alkyl group are particularly advantageous.

The activity of these products has been evaluated in a predictive testfor this kind of activity that consists of evaluating animal locomotoractivity. It is carried out on groups of 10 mice having received thetesting compounds per os (8 mg/kg) 15 minutes before the injection ofphencyclidine (4 mg/kg). The animals are placed in an “open field”divided into 9 equal squares. A camera records their activity during 25minutes, locomotor activity being expressed as the number of squarescrossed per minute.

Among the above-mentioned derivatives, the following known compounds,with the Chemical Abstracts Service registry number (CAS No.) given inbrackets,

-   isopropyl R(+)-2-amino-3-hydroxypropanoate (CAS No. 117426-05-8) and    the pharmaceutically acceptable salts thereof, particularly    hydrochloride (CAS No. 104055-30-3),-   benzyl R(+)-2-amino-3-hydroxypropanoate (CAS No. 133099-79-3) and    pharmaceutically acceptable salts thereof, particularly    hydrochloride (CAS No. 151651-44-4),-   N-[R(+)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoic acid (CAS    No. 61427-68-7),    and pharmaceutically acceptable salts thereof,-   N-[S(−)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoic acid (CAS    No. 1115-50-0), and pharmaceutically acceptable salts thereof,-   N-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoic    acid (CAS No. 17460-58-1), and pharmaceutically acceptable salts    thereof,-   N-acetyl-R(+)-2-amino-3-hydroxypropanoic acid (CAS No. 152612-69-6),    and pharmaceutically acceptable salts thereof,-   N-benzyl-R(+)-2-amino-3-hydroxypropanoic acid (CAS No. 106910-77-4),    and pharmaceutically acceptable salts thereof,-   ethyl    R(+)-N-[(1-methyl-3-oxo)-1-buten-1-yl]-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   R(+)-N-(3-phenyl)propyl-2-amino-3-hydroxypropanoic acid and    pharmaceutically acceptable salts thereof,-   ethyl R(+)-N-(3-phenyl)propyl-2-amino-3-hydroxypropanoate and    pharmaceutically acceptable salts thereof,    are particularly advantageous for the intended use.

Compounds of formula I, particularly the above-mentioned specificcompounds, are administered to patients in need of an increase ofglycinergic transmission at a daily dose which does not exceed 10 g perday and which is advantageously between 200 and 7500 mg and moreadvantageously between 250-5000 mg. The preferred doses, 500 to 3000 mgor 750 to 2000 mg, allow a good improvement of glycinergic transmissionand also improve the negative symptoms of schizophrenia, the symptoms ofAlzheimer's disease and behavior in cases of autism.

For administration to patients, compounds which are useful as activeprinciples destined to improve glycinergic transmission are included inpharmaceutical compositions formulated in unit dosages containing 10 mgto 1200 mg, advantageously 50 to 1000 mg of active principle.

According to another of its aspects, the present invention provides apharmaceutical composition comprising, as active principle, apharmacologically effective dose of a R(+)-2-amino-3-hydroxypropanoicacid derivative of formula II

wherein Rb is a hydrogen, Rb′ is a hydrogen, a straight or branchedchain (C₃-C₆)alkenyl, 3-oxo(C₄-C₆)alkyl or 3-oxo(C₄-C₆)alken-2-yl group,a phenyl(C₁-C₆)alkyl, phenyl(C₂-C₆)alkenyl, (C₂-C₆)alcanoyl,gem-diphenyl(C₁-C₆)alkyl, gem-diphenyl(C₂-C₆)alkenyl, (C₃-C₆)alkenoyl,N-(C₂-C₆)alcanoyl-R(+)-2-aminopropionyl,N-(C₂-C₆)alcanoyl-S(−)-2-aminopropionyl,N-benzyloxycarbonyl-R(+)-2-aminopropionyl,N-benzyloxycarbonyl-S(−)-2-aminopropionyl, R(+)-2,6-diamino-n-hexanoyl,S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-(C₂-C₆)alcanoyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-(C₂-C₆)alcanoyl-S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-S(−)-2,6-diamino-n-hexanoyl group; or Rb andRb′ are together a phenyl(C₁-C₆)alkylidene orgem-diphenyl(C₁-C₆)alkylidene group; Rb″ is hydrogen, a straight orbranched chain (C₁-C₆)alkyl group or a (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,phenyl(C₁-C₂)alkyl, phenacetyl or phenyl group, the phenyl group orgroups present in the Rb, Rb′ and Rb″ substituents being non-substitutedor substituted by a halogen atom or by a hydroxy, (C₁-C₃)alkoxy, cyano,nitro or acetyl group, with the proviso that, when Rb and Rb′ are bothH, then Rb″ is other than hydrogen, methyl, ethyl or non-substitutedbenzyl and that, when Rb is hydrogen and Rb′ is a non-substitutedbenzyl, N-benzyloxycarbonyl-S(−)-2-aminopropionyl, R(+)-2-aminopropionylor S(−)-2-aminopropionyl, then Rb″ is different to hydrogen; or of apharmaceutically acceptable salt thereof, in admixture with apharmaceutically acceptable carrier.

Among the compounds of formula II where Rb′ is agem-diphenyl(C₁-C₆)alkyl group, those in which Rb′ is aω-diphenyl(C₂-C₆)alkyl group, are particularly advantageous.

Among the above-mentioned active principles of formula II,

-   2-oxo-2-phenylethyl R(+)-2-amino-3-hydroxypropanoate and    pharmaceutically acceptable salts thereof,-   cyclopropylmethyl R(+)-2-amino-3-hydroxypropanoate and    pharmaceutically acceptable salts thereof,-   4-acetylphenyl R(+)-2-amino-3-hydroxypropanoate and pharmaceutically    acceptable salts thereof,-   N-[2-[R(+)-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoic acid    and pharmaceutically acceptable salts thereof,-   N-[2-[S(−)-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoic    acid, and pharmaceutically acceptable salts thereof,-   ethyl N-[S(−)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoate and    pharmaceutically acceptable salts thereof,-   methyl    N-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   ethyl    N-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   N-[2-[R(+)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoic    acid and pharmaceutically acceptable salts thereof,-   methyl    N-[2-[R(+)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   N-[2-[S(−)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoic    acid and pharmaceutically acceptable salts thereof,-   methyl    N-[2-[R(+)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   methyl    N-[2-[S(−)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   ethyl    N-[2-[R(+)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   ethyl N-benzyl-R(+)-2-amino-3-hydroxypropanoate and pharmaceutically    acceptable salts thereof,-   ethyl    R(+)-N-[(1-methyl-3-oxo)-1-buten-1-yl]-2-amino-3-hydroxypropanoate    and pharmaceutically acceptable salts thereof,-   R(+)-N-(3-phenyl)propyl-2-amino-3-hydroxypropanoic acid and    pharmaceutically acceptable salts thereof,-   ethyl R(+)-N-(3-phenyl)propyl-2-amino-3-hydroxypropanoate and    pharmaceutically acceptable salts thereof,    are particularly interesting active principles.

In said pharmaceutical compositions for oral, sublingual, subcutaneous,intramuscular, transdermal or rectal administration, the activeprinciple can be administrated in the most appropriate dosage unit inadmixture with traditional pharmaceutical carriers in animals andhumans. Suitable administration unit forms comprise oral forms such astablets, capsules, powders, granulates and oral solutions orsuspensions, sublingual and buccal administration forms or parenteral orrectal administration forms.

According to a further of its aspects, the present invention providesnew R(+)-2-amino-3-hydroxypropanoic acid derivatives of formula III

wherein R is a hydrogen; R′ is a hydrogen, phenyl(C₂-C₆)alkenyl,gem-diphenyl(C₁-C₆)alkyl other than benzhydryl,gem-diphenyl(C₂-C₆)alkenyl; or R and R′ are together aphenyl(C₁-C₆)alkylidene or gem-diphenyl(C₁-C₆)alkylidene group; R″ is ahydrogen or a (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,phenyl(C₁-C₂)alkyl, phenacetyl or phenyl group; the phenyl group orgroups being non-substituted or substituted by a halogen atom or by ahydroxy, (C₁-C₃)alkoxy, cyano, nitro or acetyl group, with the provisothat, when R and R′ are both hydrogens, then R″ is other than hydrogen;and the pharmaceutically acceptable salts thereof.

Among the compounds of formula III in which R′ is agem-diphenyl(C₁-C₆)alkyl group other than benzhydryl, those in which R′is a ω-diphenyl(C₂-C₆)alkyl group are particularly advantageous.

Among the compounds of formula III,

-   R(+)-N-(4,4-diphenyl)butyl-2-amino-3-hydroxypropanoic acid and    pharmaceutically acceptable salts thereof,-   R(+)-N-[(4,4-diphenyl)-3-butenyl]-2-amino-3-hydroxypropanoic acid    and pharmaceutically acceptable salts thereof, and-   R(+)-N-[(α-phenyl-(2-hydroxy)benzylidene]-2-amino-3-hydroxypropanoic    acid and pharmaceutically acceptable salts thereof    are particularly advantageous.

The compounds of the invention, which are N-substitution derivatives ofthe R(+)-2-amino-3-hydroxypropanoic acid or of the esters thereof, andthe pharmaceutically acceptable salts thereof, are synthesized accordingto the traditional preparation methods of amino acid esters or ofN-substituted amino acid derivatives and of their esters.

R(+)-2-amino-3-hydroxypropanoic acid esters can be obtained by reactinga D-serine functional derivative with an esterifying alcohol or phenolor by saponification in position 4 of the methyl or ethyl(R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-carboxylate,esterification of the(R)-3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-carboxylic acid byreaction of a functional derivative thereof with the esterifying alcoholor phenol in the presence of a proton acceptor, for example of atertiary base such as 4-dimethylaminopyridine, methylmorpholine,ethylmorpholine or diisopropylamine, and saponification of tert-butylester with trifluoroacetic acid which concurrently affords thedecomposition of the oxazolidine cycle and the formation of the desiredR(+)-2-amino-3-hydroxypropanoic acid ester in form of itstrifluoroacetic acid salt which, in its turn, can be neutralized orconverted into another salt. The esters thus obtained can be transformedinto N-substitution derivatives thereof and into pharmaceuticallyacceptable salts thereof.

N-monosubstitution can be carried out by reacting theR(+)-2-amino-3-hydroxypropanoic acid ester with an halide of formula:Ra′-Hal (IVa), Rb′-Hal (IVb) or R′-Hal (IV)wherein Ra′, Rb′ and R′ have the above stated meanings, in the presenceof an organic tertiary base such as 4-dimethylaminopyridine, 4-methyl-or 4-ethylmorpholine, or of an inorganic base such as an alkalinebicarbonate such as sodium hydrogen carbonate.

When Ra′, Rb′ and R′ are optionally substituted alcanoyl groups, thecorresponding acyl halide can be replaced by another functionalderivative such as a mixed anhydride, an active ester or the free acidform, appropriately activated for example by dicyclohexylcarbodiimide.If the alcanoyl group is substituted on the alkyl with an amino group,the latter will be suitably protected by one of the conventionalprotecting groups of the peptide chemistry, for example by abenzyloxycarbonyl group.

In a similar way, the above halides, when Ra′, Rb′ or R′ are other thanan alcanoyl group, can be replaced by a compound of formulaRa′-X (IVa′), Rb′-X (IVb′) or R′-X (IV′)wherein X represents a leaving group such as an alcanesulphonyloxyradical, such as a methanesulphonyloxy, or a benzenesulphonyloxyradical, the latter being non-substituted or substituted on the benzenecycle preferably with a methyl group, such as p-toluenesulphonyloxy.

Compounds of formula I, II or II, wherein Ra or Rb or R is hydrogen andRa′ or Rb′ or R′ is other than an alcanoyl group, can also be preparedby reductive amination by reacting the aldehyde or ketone correspondingto the compound Ra′-H or Rb′-H or R′-H with D-serine, preferably in theform of one of its esters, in the presence of a reducing agent such assodium cyanoborohydride. If the ester has a group that is sensitive toreducing agents, for example a ketone, this group is suitably protectedas a ketal or enol ether thereof.

The preparation of the compounds of formula I, II or III, wherein Ra andRa′, or Rb and Rb′, or, respectively, R and R′, together, form aphenyl(C₁-C₆)alkylidene group, is carried out by reacting D-serine or anester thereof with a phenyl(C₁-C₆)carboxaldehyde under the preparationconditions of Schiff bases. In a similar way, the compounds of formulaI, II or III, where Ra and Ra′, or Rb and Rb′, or R and R′, togetherform a gem-diphenyl(C₁-C₆)alkylidene group, are prepared by reactingD-serine or one of the esters thereof with a benzophenone, if thedesired product has the formula I, II or III where Ra and Ra′, or Rb andRb′, or R and R′ together form a gem-diphenyl(C₁)alkyl (diphenylmethyl)group; or with a gem-diphenyl(C₂-C₆)carboxaldehyde, if the desiredproduct has the formula I, II or III where Ra and Ra′, or Rb and Rb′, orR and R′ together form a gem-diphenyl(C₂-C₆)alkyl group, according toSchiff base preparation conditions.

The word “phenyl” used in the general description above, comprises anyphenyl group that can be non-substituted or substituted by a halogenatom or by a hydroxy, (C₁-C₃)alkoxy, cyano, nitro or acetyl group.

When D-serine methyl or ethyl ester is used as starting compound, theN-substituted derivative thus obtained is an intermediate which issaponified in order to prepare a compound of formula I, II or IIIwherein Ra″, Rb″ or R″ is hydrogen, whereas the N-substituted derivativethus obtained is the final product when an ester other than the methylor ethyl ester is used as starting compound.

The R(+)-2-amino-3-hydroxypropanoic acid derivatives can be isolated inthe free form or as chemically or pharmaceutically acceptable saltsthereof. Considering the amphoteric character of the compounds of thepresent invention, the salts can be those with mineral or organic bases,for example with sodium hydroxide or trometamol, or with mineral ororganic acids such as the hydrochloride or the trifluoroacetate. In thecase of the compounds of formula I, chemically or pharmaceuticallyacceptable salts are included in the invention. The expression“chemically acceptable” refers to salts of formula I compounds that areuseful for the isolation or purification of the new products.

The following non-limitative examples illustrate the invention.

EXAMPLE 1 Cyclopropylmethyl 2-(R)-amino-3-hydroxypropanoatehydrochloride

Cyclopropylcarbinol (15 ml) is cooled to 0° C. and acetyl chloride (1.37ml) is added. After being subjected to agitation for 10 minutes at 0°C., D-serine (750 mg) is added and the solution is brought to reflux for2 hours. The reaction mixture is concentrated, recovered with apotassium carbonate saturated solution and extracted with ethyl acetate.The organic phase is dried on MgSO₄, filtered and concentrated. Theproduct is recovered in a minimum of methanol and a hydrochloric acidsolution 1N is added in ether. The solvent is vacuum evaporated toobtain the desired product as a brown solid (250 mg). Melting point:112-118° C.

RMN ¹H (CD₃OD) d 4.07 (m, 5H); 1.18 (m, 1H); 0.64 (m, 2H); 0.37 (m, 2H).

EXAMPLE 2 4-acetylphenyl 2-(R)-amino-3-hydroxypropanoatetrifluoroacetate (a) methyl3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate

The product is prepared according to the method described in the articleof P. Gamer, J. M. Park, J. Org. Chem. 1987, 52, 2361-2364.

(b) 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylic acid

Methyl 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate(3.0 g) is dissolved in a mixture of tetrahydrofurane (THF)/H₂O (3/1; 30ml), and LiOH.H₂O (684 mg) is added. After being subjected to agitationfor 3 hours at room temperature, the reaction mixture is acidified withcitric acid 1N (11 ml). THF is concentrated and the aqueous phase isextracted with ethyl acetate. The organic phase is dried on MgSO₄,filtered and concentrated to obtain the expected product as a viscousorange oil (1.36 g).

(c) 4-acetylphenyl3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate

At 0° C., 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylicacid (1.0 g) is dissolved in ethyl acetate (25 ml),dicyclohexylcarbodiimide (DCC; 1.26 g) is then added and the reactionmixture is subjected to agitation for 45 minutes at 0° C.Dimethylaminopyridine (DMAP; 100 mg) and 4′-hydroxyacetophenone (565 mg)are successively added, the reaction mixture is then left to return toroom temperature. After 5 hours of agitation, the mixture is filteredand the filtrate is washed with a sodium hydrogen carbonate saturatedsolution, then with a sodium chloride saturated solution. The organicphase is dried on MgSO₄, filtered and concentrated. The obtained orangeoil is purified by chromatography on silica to obtain the desiredproduct as a transparent oil (940 mg).

(d) 4-acetylphenyl 2-(R)-amino-3-hydroxypropanoate trifluoroacetate

Under nitrogen, 4-acetylphenyl3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate (440 mg)is dissolved in dichloromethane (15 ml), and trifluoroacetic acid (TFA;8 ml) is added. After being subjected to agitation for 1 hour, thereaction mixture is concentrated and ether is added. The formedprecipitate is filtered, then vacuum dried to obtain the desired productas a white powder (280 mg). Melting point: 115-118° C.

RMN ¹H (CD₃OD) d 8.12 (d, 2H); 7.39 (d, 2H); 4.49 (m, 1H); 4.25 (dd,1H); 4.08 (dd, 1H); 2.56 (s, 3H).

EXAMPLE 3 EthylN-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate

At 0° C., N-benzyloxycarbonyl-S(−)-alanine (3.0 g), R(+)-serine ethylester hydrochloride (2.28 g), 1-hydroxybenzotriazole hydrate (HOBt.H₂O;1.82 g) and N-ethylmorpholine (1.69 ml) are dissolved intetrahydrofurane (THF; 30 ml). Then dicyclohexylcarbodiimide (DCC) (2.91g) is added and the mixture is left to return to room temperature. Afterbeing subjected to agitation for 5 hours, the solution is filtered,rinsed with THF and the filtrate is concentrated. The residue isrecovered in dichloromethane and the organic phase is successivelywashed with a sodium carbonate saturated solution, water and a sodiumchloride saturated solution. The organic phase is dried on MgSO₄,filtered and concentrated. The obtained solid is purified bychromatography on silica to obtain the desired product as a white powder(2.5 g).

EXAMPLE 4 EthylN-[S(−)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoate hydrochloride

The ethylN-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate(1.0 g) obtained as described in example 3, is dissolved in ethanol (25ml), and a concentrated hydrochloric acid solution (0.25 ml) andpalladium on carbon (150 mg) are added. The reaction mixture is placedunder hydrogen atmosphere (P=1.3 bar) for 30 minutes, then filtered onkelite. The filtrate is dry evaporated to obtain the desired product asa beige powder (635 mg).

Melting point: 163-168° C.

RMN ¹H (CD₃OD) d 4.55 (m, 1H); 4.21 (q, 2H); 4.05 (m, 1H); 3.9 (m, 2H);1.54 (d, 3H); 1.28 (t, 3H).

EXAMPLE 5 EthylN-[2-[R(+)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate

At 0° C., N,N′-bis-benzyloxycarbonyl-R(+)-lysine (2.51 g), R(+)-serineethyl ester hydrochloride (1.03 g), HOBt.H₂O (0.82 g) andN-ethylmorpholine (0.76 ml) are dissolved in THF (30 ml). Then DCC (1.31g) is added and the medium is left to return to room temperature for 4hours. The reaction mixture is filtered on sintered material, washedwith THF then the filtrate is dry concentrated. The residue is recoveredin ethyl acetate and the organic phase is washed with a sodium carbonatesaturated solution, then with a sodium chloride saturated solution. Theorganic phase is dried on MgSO₄, filtrated and concentrated. Theobtained solid is purified by chromatography on silica to obtain thedesired product as a white solid (1.14 g). Melting point: 133-136° C.

RMN ¹H (CDCl₃) d 7.28 (brs, 10H); 6.94 (brs, NH); 5.55 (brs, NH); 5.11(s, 2H); 5.08 (s, 2H); 4.99 (brs, NH); 4.62 (m, 1H); 4.22 (q, 3H); 3.96(brs, 2H); 3.21 (m, 2H); 1.72 (m, 6H); 1.27 (t, 3H).

EXAMPLE 6 Methyl R(+)-N-(4,4-diphenyl)butyl-2-amino-3-hydroxypropanoate(a) 1,1-Diphenyl-4-bromobutene

At 0° C., cyclopropyl-diphenyl-carbinol (10.0 g) is dissolved in ahydrogen bromide solution 48% (40 ml). After being subjected toagitation for 5 hours at 0° C., the medium is diluted with water anddichloromethane, then the organic phase is washed three times withwater. The organic phase is dried on MgSO₄, filtered and concentrated toobtain the expected product as an orange oil (11.89 g).

(b) 1,1-Diphenyl-4-bromobutane

1,1-diphenyl-4-bromobutene (10.0 g) is dissolved in absolute ethanol(100 ml) and palladium on carbon (400 mg) is added. The reaction mixtureis placed under hydrogen atmosphere (P=3.3 bar) for 6 hours. The mixtureis filtered on kelite, the filtrate is concentrated to obtain thedesired product as an orange oil (9.24 g).

(c) methyl R(+)-N-(4,4-diphenyl)butyl-2-amino-3-hydroxypropanoate

D-serine ethyl ester hydrochloride (1.5 g) is dissolved indimethylformamide (DMF; 20 ml), sodium hydrogen carbonate (1.78 g) isadded and 1,1-diphenyl-4-bromobutane (3.35 g) is dissolved in DMF (5ml). The reaction mixture is raised to 85° C. for 1 hour, then vacuumconcentrated. The residue is recovered with ethyl acetate and water,then the organic phase is washed three times with a sodium chloridesaturated solution. The organic phase is dried on MgSO₄, filtered andvacuum concentrated. Purification by chromatography on silica to obtainthe desired product as a loose yellow oil (1.38 g).

EXAMPLE 7 R(+)-N-(4,4-diphenyl)butyl-2-amino-3-hydroxypropanoic acidhydrochloride

At 0° C., methyl R(+)-N-(4,4-diphenyl)butyl-2-amino-3-hydroxypropanoate(600 mg) is dissolved in a THF/H₂O mixture (3/1; 20 ml) and a sodiumhydroxide solution 5N (0.7 ml) is added. After 15 minutes at 0° C., thereaction mixture is left to return to room temperature. After 45minutes, the mixture is cooled again to 0° C., a hydrochloric acidsolution 1N (4 ml) is added, the mixture is then vacuum concentrated.The solid obtained is triturated in boiling isopropanol and the mixtureis hot filtered. After evaporation of the filtrate, the desired productis obtained as a clear yellow powder (303 mg). Melting point: 70-75° C.

RMN ¹H (CD₃OD) d 7.18 (brs, 7H); 7.05 (m, 3H); 3.88 (m, 2H); 3.83 (m,2H); 3.00 (m, 1H); 2.08 (m, 2H); 1.61 (m, 2H); 1.24 (m, 2H).

EXAMPLE 8 MethylR(+)-N-[(4,4-diphenyl)-3-butenyl]-2-amino-3-hydroxypropanoate

R(+)-serine methyl ester hydrochloride (1,0 g) is dissolved indimethylformamide (DMF), sodium hydrogen carbonate (1.08 g) and1-(4-bromo-1-phenylbut-1-enyl) benzene (2.03 g) are added. After beingsubjected to agitation overnight at room temperature the medium isvacuum concentrated. The residue is recovered in ethyl acetate then theorganic phase is washed three times with water. The organic phase isdried on MgSO₄, filtered and concentrated. The desired product isobtained as a white powder (600 mg).

EXAMPLE 9 R(+)-N-[(4,4-diphenyl)-3-butenyl]-2-amino-3-hydroxypropanoicacid hydrochloride

At 0° C., methylR(+)-N-[(4,4-diphenyl)-3-butenyl]-2-amino-3-hydroxypropanoate (600 mg)is dissolved in a mixture of THF/H₂O (3/1; 20 ml), then a sodiumhydroxide solution 5N (700 μL) is added. After being subjected toagitation for 15 minutes at 0° C., the reaction mixture is left toreturn to room temperature for 45 minutes and then the solution iscooled again to 0° C. A hydrochloric acid solution 1N (4 ml) is addedand the medium is vacuum concentrated. The white solid obtained istriturated in boiling isopropanol, then filtered. After evaporation ofthe filtrate, the desired product is obtained as a clear yellow foam(303 mg). Melting point: 130-135° C.

RMN ¹H (CD₃OD) d 7.31 (m, 3H); 7.15 (m, 6H); 6.00 (t, 1H); 3.79 (m, 3H);3.08 (m, 2H); 2.44 (m, 2H).

EXAMPLE 10 Ethyl R(+)-N-(3-phenyl)propyl-2-amino-3-hydroxypropanoate

R(+)-serine ethyl ester hydrochloride (1.0 g) is left in suspension inanhydrous methanol, the molecular sieve 4 Å and sodium cyanoborohydride(NaBH₃CN, 267 mg) are added. After being subjected to agitation for 15minutes, 3-phenylpropionaldehyde (705 μL) is added in one portion. Afterbeing subjected to agitation for 3 h30 at room temperature, the reactionmixture is filtered on sintered material and the filtrate isconcentrated. The recovered viscous transparent oil (1.95 g) is purifiedby chromatography on silica to obtain a loose clear yellow oil (900 mg).The residue is recovered with a minimum of ether and a hydrochloric acidsolution 1N is added in ether (6 ml). The precipitate formed isfiltered, then dried to obtain the desired product as a white solid (990mg). Melting point: 102-107° C.

RMN ¹H (CD₃OD) d 7.25 (m, 5H); 4.30 (q, 2H); 4.11 (m, 1H); 3.9 (m, 2H);3.29 (m, 1H); 3.08 (m, 2H); 2.71 (t, 2H); 2.05 (m, 2H); 1.38 (t, 3H).

EXAMPLE 11 R(+)-N-(3-phenyl)propyl-2-amino-3-hydroxypropanoic acidhydrochloride

The ethyl R(+)-N-(3-phenyl)propyl-2-amino-3-hydroxypropanoate of example10 (600 mg) is dissolved in a mixture of THF/H₂O (3/1; 20 ml) andLiOH.H₂O (175 mg) is added. After being subjected to agitation overnightat room temperature, the THF is concentrated and a hydrochloric acidsolution 1N (2 ml) is added. The precipitate formed is filtered, washedin water, then dried in a vacuum oven overnight to obtain the desiredproduct as a white solid (290 mg). Melting point: 190-196° C.

RMN ¹H (DMSO) d 7.25 (m, 5H); 3.73 (m, 1H); 3.62 (m, 1H); 3.20 (m, 1H);2.85 (m, 2H); 2.58 (t, 2H); 1.90 (t, 2H).

EXAMPLE 12 EthylR(+)-N-[(]-methyl-3-oxo)-1-buten-1-yl]-2-amino-3-hydroxypropanoate

R(+)-serine ethyl ester hydrochloride (3.0 g) is dissolved in methanol(150 ml), 5 spatulas of molecular sieve 4 Å and then acetylacetone (2.55ml) are added and the mixture is brought to reflux overnight. Thesolution is filtered on Kelite, rinsed with methanol and the filtrate isdry evaporated. The residue is recovered with ethyl acetate, ether isadded, the filtrate is triturated, filtered and concentrated.Purification by chromatography on silica to obtain the desired productas a white solid (1.21 g). Melting point: 78° C.

RMN ¹H (CDCl₃) d 11.00 (d, 1H); 5.00 (s, 1H); 4.23 (m, 4H); 3.94 (m,2H); 1.95 (m, 6H); 1.27 (t, 3H).

EXAMPLE 13R(+)-N-[α-phenyl-(2-hydroxy)benzylidene]-2-amino-3-hydroxypropanoic acid

Under nitrogen, R(+)-serine (1.0 g), o-hydroxybenzophenone (940 mg),sodium methanolate (512 mg) are dissolved in ethanol (50 ml) and thereaction mixture is brought to reflux for 3 hours. The medium is vacuumconcentrated and recovered in ether. A concentrated citric acid solutionis added and the aqueous phase is extracted with ether. The organicphase is dried on MgSO₄, filtered and concentrated. The residue isrecovered in a minimum of ether, triturated and filtered to obtain thedesired product as a yellow powder (610 mg). Melting point: 170° C.

RMN ¹H (CD₃OD) d 7.58 (m, 3H); 7.34 (m, 3H); 6.95 (m, 1H); 6.82 (m, 1H);6.67 (m, 1H); 4.17 (m, 1H); 3.95 (m, 2H).

1. A method for treating cognitive disorders or mnestic disorders whichaccompany CNS diseases, comprising administering to a patient aR(+)-2-amino-3-hydroxypropanoic acid derivative of formula I

wherein Ra is a hydrogen; Ra′ is a hydrogen, a straight or branchedchain (C₃-C₆)alkenyl, 3-oxo(C₄-C₆)alkyl, 3-oxo(C₄-C₆)alken-2-yl group, aphenyl(C₁-C₆)alkyl, phenyl(C₂-C₆)alkenyl, gem-diphenyl(C₁-C₆)alkyl,gem-diphenyl(C₂-C₆)alkenyl, R(+)-2-aminopropionyl,S(−)-2-aminopropionyl, N-(C₂-C₆)alcanoyl-R(+)-2-aminopropionyl,N-(C₂-C₆)alcanoyl-S(−)-2-aminopropionyl,N-benzyloxycarbonyl-R(+)-2-aminopropionyl,N-benzyloxycarbonyl-S(−)-2-aminopropionyl, R(+)-2,6-diamino-n-hexanoyl,S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-(C₂-C₆)alcanoyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-(C₂-C₆)alcanoyl-S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-S(−)-2,6-diamino-n-hexanoyl group; or Ra andRa′ are together a phenyl(C₁-C₆)alkylydene orgem-diphenyl(C₁-C₆)alkylidene group; Ra″ is a hydrogen, a straight orbranched chain (C₁-C₆)alkyl group or a (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,phenyl(C₁-C₂)alkyl or phenacetyl group; the phenyl group or groupspresent in the substituents Ra, Ra′ and Ra″ being non-substituted orsubstituted by a halogen atom or by a hydroxy, (C₁-C₃)alkoxy, cyano,nitro or acetyl group; with the proviso that, when Ra and Ra′ are bothH, then Ra″ is other than a hydrogen, (C₁-C₆)alkyl or non-substitutedbenzyl; or of one of its pharmaceutically acceptable salts.
 2. Themethod according to claim 1, wherein said CNS disease is schizophrenia.3. The method according to claim 1, wherein said CNS disease is autism.4. The method according to claim 1, wherein said CNS disease isAlzheimer's disease.
 5. The method according to claim 1, wherein saidR(+)-2-amino-3-hydroxypropanoic acid derivative is selected from thegroup consisting ofN-[R(+)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoic acid, thepharmaceutically acceptable salts thereof,N-[S(−)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoic acid, thepharmaceutically acceptable salts thereof,N-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoicacid, the pharmaceutically acceptable salts thereof,N-benzyl-R(+)-2-amino-3-hydroxypropanoic acid and pharmaceuticallyacceptable salts thereof.
 6. A pharmaceutical composition comprising apharmaceutically effective dose of a R(+)-2-amino-3-hydroxypropanoicacid derivative of formula II

wherein Rb is a hydrogen; Rb′ is a hydrogen, a straight or branchedchain (C₃-C₆)alkenyl, 3-oxo(C₄-C₆)alkyl, 3-oxo(C₄-C₆)alken-2-yl group, aphenyl(C₁-C₆)alkyl, phenyl(C₂-C₆)alkenyl, gem-diphenyl(C₁-C₆)alkyl,gem-diphenyl(C₂-C₆)alkenyl, N-(C₂-C₆)alcanoyl-R(+)-2-aminopropionyl,N-(C₂-C₆)alcanoyl-S(−)-2-aminopropionyl,N-benzyloxycarbonyl-R(+)-2-aminopropionyl,N-benzyloxycarbonyl-S(−)-2-aminopropionyl, R(+)-2,6-diamino-n-hexanoyl,S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-(C₂-C₆)alcanoyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-(C₂-C₆)alcanoyl-S(−)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-R(+)-2,6-diamino-n-hexanoyl,N,N′-bis-benzyloxycarbonyl-S(−)-2,6-diamino-n-hexanoyl group; or Rb andRb′, are together a phenyl(C₁-C₆)alkylydene orgem-diphenyl(C₁-C₆)alkylidene group; Rb″ is a hydrogen, a straight orbranched chain (C₁-C₆)alkyl group or a (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,phenyl(C₁-C₂)alkyl or phenacetyl group; the phenyl group or groupspresent in the Rb, Rb′ and Rb″ substituents being non-substituted orsubstituted by a halogen atom or by a hydroxy, (C₁-C₃)alkoxy, cyano,nitro or acetyl group; with the proviso that, when Rb and Rb′ are bothH, then Rb″ is other than a hydrogen, (C₁-C₆)alkyl or non-substitutedbenzyl and that, when Rb is a hydrogen and Rb′ is a non-substitutedbenzyl, a N-benzyloxycarbonyl-S(−)-2-aminopropionyl, aR(+)-2-aminopropionyl or S(−)-2-aminopropionyl, then Rb″ is other thanhydrogen; or one of its pharmaceutically acceptable salts, in admixturewith a pharmaceutically acceptable carrier.
 7. The pharmaceuticalcomposition according to claim 6, wherein saidR(+)-2-amino-3-hydroxypropanoic acid derivative of formula II isselected from the group comprising 2-oxo-2-phenylethylR(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable saltsthereof, cyclopropylmethyl R(+)-2-amino-3-hydroxypropanoate, thepharmaceutically acceptable salts thereof, 4-acetylphenylR(+)-2-amino-3-hydroxypropanoate, the pharmaceutically acceptable saltsthereof, N-[2-[R(+)-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoicacid, the pharmaceutically acceptable salts thereof,N-[2-[S(−)-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoic acid,the pharmaceutically acceptable salts thereof, ethylN-[S(−)-2-aminopropionyl]-R(+)-2-amino-3-hydroxypropanoate, thepharmaceutically acceptable salts thereof, methylN-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate,the pharmaceutically acceptable salts thereof, ethylN-[2-[S(−)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate,the pharmaceutically acceptable salts thereof,N-[2-[R(+)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoicacid, the pharmaceutically acceptable salts thereof, methylN-[2-[R(+)-benzyloxycarbonylamino]propionyl]-R(+)-2-amino-3-hydroxypropanoate,the pharmaceutically acceptable salts thereof,N-[2-[S(−)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoicacid, the pharmaceutically acceptable salts thereof, methylN-[2-[R(+)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate,the pharmaceutically acceptable salts thereof, methylN-[2-[S(−)-N,N′-bis-benzyloxycarbonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate,the pharmaceutically acceptable salts thereof, ethylN-[2-[R(+)-N,N′-bis-benzyloxycabonyl-2,6-diaminohexanoyl]-R(+)-2-amino-3-hydroxypropanoate,the pharmaceutically acceptable salts thereof, ethylN-benzyl-R(+)-2-amino-3-hydroxypropanoate and pharmaceuticallyacceptable salts thereof.
 8. A R(+)-2-amino-3-hydroxypropanoic acidderivative of formula III

wherein R is a hydrogen; R′ is a hydrogen, a phenyl(C₂-C₆)alkenyl,gem-diphenyl(C₁-C₆)alkyl group other than benzhydryl,gem-diphenyl(C₂-C₆)alkenyl; or R and R′, together, form aphenyl(C₁-C₆)alkylidene or gem-diphenyl(C₁-C₆)alkylidene group; R″ is ahydrogen or a (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,phenyl(C₁-C₂)alkyl or phenacetyl group; the phenyl group or groups beingnon-substituted or substituted by a halogen atom or by a hydroxy,(C₁-C₃)alkoxy, cyano, nitro or acetyl group; with the proviso that, whenR and R′ are both hydrogen, then R″ is other than a hydrogen,(C₁-C₆)alkyl or non-substituted benzyl; or one of its pharmaceuticallyacceptable salts.
 9. The R(+)-2-amino-3-hydroxypropanoic acid derivativeaccording to claim 8, where R′ is a ω-diphenyl(C₂-C₆)alkyl group. 10.R(+)-N-(4,4-diphenyl)butyl-2-amino-3-hydroxypropanoic acid or apharmaceutically acceptable salt thereof. 11.R(+)-N-[(4,4-diphenyl)-3-butenyl]-2-amino-3-hydroxypropanoic acid or apharmaceutically acceptable salt thereof. 12.R(+)-N-[α-phenyl-(2-hydroxy)benzylidene]-2-amino-3-hydroxypropanoic acidor a pharmaceutically acceptable salt thereof.
 13. The method accordingto claim 1, wherein said treatment increases glycinergic transmission insaid patient.